Focal segmental glomerulosclerosis (FSGS) is a clinical-pathologic syndrome characterized by the accumulation of fibrotic proteins in glomeruli, initially involving only some glomeruli (focal) and involving portions (segments) of the affected glomeruli. FSGS can be classified as follows: idiopathic FSGS, HIV-associated FSGS, hyperfiltation FSGS (due to reduced renal mass, renal toxins, or obesity), and genetic causes. In order to define the molecular mechanisms responsible for HIV-associated FSGS, we have established a line of mice in which transgene expression can be regulated in the glomerular podocyte using an tetracycline-regulated system. We have shown that expression is tightly regulated and is restricted to the podocyte. We have used this system to express the HIV-1 accessory protein Vpr in the podocyte. These mice develop proteinuria beginning 4 weeks after treatment with tetracycline and with 95% of mice developing proteinuria by 20 weeks. FSGS appears at 8 weeks, progressing to global glomerulosclerosis and end-stage kidney disease. Podocyte phenotype is abnormal, with reduced expression of the differentiation marker synaptopodin and de novo expression of the injury marker desmin. Increased cell proliferation is present in the glomerular tuft, parietal epithelum, and tubular epithelium. These results demonstrate that Vpr is sufficient to induce HIV-associated FSGS in transgenic mice. Pirfenidone is an orally-active, small molecule inhibitor of fibrosis, whose mechanism of action has not been well-defined but might involve inhibiting production of TGF-beta. We have carried out an open label, phase II study for FSGS patients with declining renal function. The study design compares the rate of glomerular filtration rate (GFR) decline during a baseline period in which blood pressure is controlled and the patient receives angiotensin antagonist medication (ACE inhibitor or angiotensin receptor blocker) with the rate of GFR decline while on pirfenidone therapy plus angiotensin antagonist medication. We have enrolled 20 patients, who receive treatment for at least one year but may continue pirfenidone thereafter. In the first 15 patients, after a mean follow-up of 11 months, the GFR decline rate improved from 0.81 +/- 16.5 (mean,SD) ml/min/mo during the baseline period to 0.56 +/- 0.47 ml/min/mo while receiving pirfenidone (P=0.03). This represents an improvement of approximately 30%, an effect size comparable to that of ACE inhibitors in patients with diabetic nephropathy (another disease characterized by glomerulosclerosis). We are discussing with collaborators, including InterMune, which holds the license for pirfenidone, plans to carry out a multi-center, randomized, placebo-controlled phase III study to confirm efficacy and establish minimum effective dose. Therapy with daily prednisone induces remission in approximately 30% of FSGS patients, but with substantial morbidity. We have carried out an open label pilot study of pulse oral dexamethasone for idiopathic FSGS. We hypothesize that 8 months of pulse dexamethasone treatment will have equal or greater efficacy compared to daily prednisone with reduced toxicity. We have enrolled 15 patient. Nadir proteinuria indicated a complete remission (proteinuria <0.3 g/d) in 1 patient and a partial remission (<2 g/d) in 5 patients, for an overall response rate of 40%. We have not observed significant toxicity despite extensive evaluation. Based upon these promising results, we have initiated a new trial comparing a more intensive steroid regimen for children and adults with minimal change disease and FSGS. The treatment is oral dexamethasone at a dose of 50 mg/m2 for the weeks 1-16 and 25 mg/m2 for weeks 17-48. Patients are randomized to 2 doses every 2 weeks and 4 doses every 4 weeks, so that all patients receive 48 doses over 48 weeks.